ABSTRACT Obesity has been shown to confer increased risk of coronary artery disease and stroke. However, recent data suggest that there are some obese persons who appear to be metabolically healthy. These individuals may not be at any increased risk of cardiovascular disease and may, in fact, have adverse metabolic reactions to weight loss treatments. Whether obesity subtypes are at differential risk of cerebrovascular disease and whether this risk is associated with cytokines from adipocytes is not known. This application will examine whether obesity subtypes exhibit differential risk for ischemic stroke, and consider mechanisms underlying these differential risks including levels of high-molecular weight (HMW) adiponectin. Data from the Women's Health Initiative Observational Cohort (WHI-OS) NINDS-funded nested stroke case-control study, [unreadable]Hormones and Biomarkers Predicting Stroke[unreadable] (HaBPS) will be used. The specific aims are: 1.) To examine the association between baseline obesity subtypes (obese with metabolic abnormalities, obese but metabolically healthy, non-obese but with metabolic abnormalities, non-obese and metabolically healthy) and ischemic stroke risk, 2.) To examine the association between HMW adiponectin levels and obesity subtypes and determine whether adiponectin levels may partially explain any increased stroke risk associated with metabolic obesity, and 3.) To examine racial differences in obesity subtypes and HMW adiponectin levels, and the extent to which adiponectin levels explain any racial differences in obesity subtypes. Examination of the stroke risk associated with obesity subtypes, as well as the specific adipose endocrine factors which may underlie the differential risk will provide information vital to distinguishing between women who will likely suffer obesity-associated cerebrovascular complications, such as stroke, and women who will not. As the obesity epidemic continues to grow and health care expenditures increase, an understanding of these relationships will be critical to further development of anti-obesity therapies, and targeting of those therapies to the individuals who most need it and in whom it will be most effective. NARRATIVE Given the high rate of stroke and subsequent disability in the U.S., and the high prevalence of obesity, this study will provide information essential to stroke prevention, the development of obesity treatment strategies, and evaluation into their appropriate indications. Should obesity phenotypes be found to be at differential stroke risk and the causal factors underlying such risk discovered, further research could examine these factors not only as future targets of intervention, but also as clinical tools for monitoring the success of anti-obesity treatments. Therefore, this application could have a significant impact on stroke prevention as it relates to appropriate treatment indications for obesity.